Urticaria is a common skin disorder involving mast cell activation and degranulation. Urticaria is classified according to its chronicity into acute and chronic forms. It may occur spontaneously or on exposure to a physical factor. In the latter case, the urticaria is classified as a physical urticaria. Physical urticaria may be induced by mechanical and applied pressure, exercise, or exposure to cold, heat, sun, water, or vibration. The pathologic basis of physicial urticarias in general remains unclear and a genetic basis for these disorders has not been elucidated. The purpose of this project is to investigate the mast cell dependent pathogenic mechanisms of physical urticaria, both to better understand how to manage urticarial inflammation and to explore the consequences of mast cell degranulation in human tissues. In these studies, adult and pediatric patients undergo standard challenge testing to verify their urticaria. Blood samples are obtained for the investigation of molecular and genetic pathways involved in the disease process. Following the clinical induction of urticarial manifestations, additional blood samples are collected to determine soluble mediators involved in pathogenesis. Photographic imaging studies are performed during challenge testing. Skin biopsies are obtained prior to and following challenge testing and are analyzed for biochemical and histological markers. Since the inception of the physical urticaria protocol in 2009, we have enrolled over 118 patients and 25 healthy subjects. All patients safely underwent challenge testing based on their history. Blood samples and skin biopsies have been collected and stored for biochemical, molecular and, when applicable, genetic analysis. Mast cell degranulation was verified by skin biopsy. The majority of the patients were challenge positive to either cold-induced, cholinergic, dermatographism, solar or vibratory urticaria. In a prospective survey of 76 subjects referred for physical urticaria challenge testing on this study, we explored the consistency between a history of physical urticaria and results of challenge testing. A total of 294 challenge tests were performed on these patients, most of which were on medications and had altered their life style significantly to avoid reactions. We found that 38% of the 76 patients were challenge negative to the presenting diagnosis and 28% were found to be negative to all challenge testing performed. These findings were generally quite surprising to the patients and enabled those in the negative challenge group to decrease medication use and in some cases, with proper monitoring, to stop medicine and resume normal activities. Most patients (57 of 76) were reevaluated one year after their initial assessment and were unchanged, noting that of the 19 patients that were initially negative to challenge, all remained negative. These results support the great value and reproducibility of challenge testing in patients with a history of a physical urticaria. Of the 38 patients that were initially positive to challenge testing, 4 patients (11%) had resolution of symptoms. These findings highlight the value of objective testing in patients with a history of a physically induced urticaria in order to accurately assess disease status and therapy. This study, entitled Dissociation Between History and Challenge in a Subset of Patients with Physical Urticarias, is in press in J Allergy Clin Immunol Pract (2014). In an effort to accurately diagnose urticarial skin lesions we performed a retrospective chart review of 299 subjects with mastocytosis and identified 24 subjects that were diagnosed with Telangiectasia macularis eruptive perstans (TMEP). We determined that the diagnosis of TMEP was not clinically substantiated in any of these patients, the majority of our cohort was ultimately diagnosed with indolent systemic and that highly vascularized UP more accurately describes the pigmented macular lesions that localize with observable telangiectasia (published in J Allergy Clin Immunol Pract (2014). In order to further highlight the utility of challenge testing, we also reported a historical and pictorial description of two cases of solar urticaria, which is a rare form of physical urticaria. The history and ultraviolet (UVA, UVB) and visible light challenge testing results from these cases are depicted in the Images in Allergy section of J Allergy Clin Immunol Pract (2015). Phototesting as performed in these cases at the bedside, aids in the identification of the wavelength that elicits solar manifestations and helps to characterize the nature and intensity of the reaction, which is helpful for selecting treatment. We identified a two large Lebanese families with vibratory urticaria, a rare condition in which sustained vibration against the skin induces both a localized hive and systemic manifestations such as facial flushing. The findings of acute onset of symptoms with concurrent peripheral histamine release in affected family members implicates mast cell degranulation in the pathogenesis. This was also supported by increased staining of tryptase, a component of mast cell granular contents, in post-vibration patient skin samples compared to controls. Through linkage analysis and exome sequencing we identified a missense mutation that segregates with vibratory urticaria in these kindreds but was absent from variant databases and 1000 ancestry-matched controls. The gene which harbors this mutation encodes an adhesion G-protein coupled that was highly expressed in human mast cells with a unique ligand ubiquitously found in the skin. Patient-derived primary mast cells, when adhered through this ligand and vibrated, degranulate. Likewise, transfected human LAD2 mast cells expressing this mutation showed greater degranulation in response to vibration than control cells. Our findings suggest a genetic basis for an IgE independent mechanism for mast cell degranulation though a vibratory stimulus. A manuscript detailing the results of this study is in review.